Squamous cell carcinoma (SCC) of the tongue is one of the most common cancers in the oral and maxillofacial region. The incidence of occult cervical lymph node metastases (OCLNM) is high in SCC of the tongue.1 The presence of cervical lymph node metastases is one of the most important prognostic factors for patients with SCC of the tongue.2 There is no debate that node-positive (N+) patients with SCC of the tongue should undergo therapeutic neck dissection. However, for the node-negative (cN0) neck, whether selective neck dissection (SND) should be performed or not and the involved levels of neck dissection are still controversial.3,4 The purpose of this study was to provide clinical evidence for SND in management of cN0 patients by analyzing the characteristics of OCLNM in 100 patients with SCC of the tongue about the distribution, time to metastasis and other correlated factors.
In the Department of Oral and Maxillofacial Surgery, the Ninth People’s Hospital, Shanghai Jiao Tong University, from September 2002 to September 2006, 100 consecutive patients with cN0 SCC of the tongue were retrospectively reviewed. The clinical and pathological data of all patients were complete and no patients underwent radiotherapy preoperatively. The diagnostic criteria for cN0 patients were:5 (A) the cervical lymph node was not palpated or the node ≤10 mm in axial diameter by clinical examination with the texture of the node soft, (B) the enlarged node was not observed by imaging examination or the node >10 mm in axial diameter without central necrosis and surrounding rim of enhancement.
The tumor sites, diameters of tumor, depths of invasion, forms of growth, pathological degree, degree of differentiation, T classification, distribution of OCLNM and neck dissection in all patients were reviewed. The relation between OCLNM and these correlation factors were analyzed.
The times before cervical metastases emerged were divided into 5 groups: <6 months, 6–12 months, 13–18 months, 19–24 months, and >24 months. The tumors were divided by their largest diameters into 2 groups by ≤3 cm and >3 cm, according to Han’s method. 6 The forms of tumor growth included exophytic form, ulcerative form and infiltrative form. Tumor sites included 1/3 anterior tongue, 1/3 middle-tongue and 1/3 posterior tongue. Among them, 1/3 anterior tongue and 1/3 middle-tongue were equal to the mobile tongue, 1/3 posterior tongue was equal to the base of tongue. T classifications were according to the T classification of the American Joint Committee on Cancer (AJCC) in 2002.7 Histological grades were based on the classification proposed by the World Health Organization in 1997. Depths of invasion were gained by reviewing the paraffin sections (hematoxylin and eosin staining) according to Yuen’s method,8 the outcomes were divided into 3 groups by mucosal layer, submucosal layer and muscular layer. The neck treatments included radical neck dissection (RND, levels I-V), functional neck dissection (FND, levels I-V) in which the accessory nerves and the sternocleidomastoid muscles are not excised,9 supraomohyoid neck dissection (SOND, levels I—III) and “wait and see” policy.
All statistical analysis was performed using the SAS 9.13 statistical package. The contributions of changed trends to OCLNM in all patients were tested by Cochran-Armitage trend test according to pathological grade, T stage, degree of differentiation and depth of invasion. Fisher’s exact test was used to determine the relationship between various clinicopathological factors and occult lymph node metastasis in tongue cancer patients. P values of <0.05 were considered statistically significant.
Analysis of clinical data
All patients were reviewed by one of two head and neck oncologists (Dr. YE or Dr. ZHU) during the period of follow-up. The average follow-up period was 2.83 years (ranging from 1–5 years). Among 100 patients, there were 65 males and 35 females, and the median age was 55 years (ranged from 20 years to 83 years). According to clinical stage, there were 25 patients in T1 classification, 60 patients in T2 classification, 10 patients in T3 classification, and 5 patients in T4 classification. For degree of differentiation, there were 76 patients with well differentiated carcinoma (G1), 19 patients with moderately differentiated carcinoma (G2), and 5 patients with poorly differentiated carcinoma (G3). During the period of follow-up, cervical lymph node metastases were found in 22 patients (group pN+) and not found in 78 patients (group pN-).
Incidences, distribution levels, metastatic time of OCLNM in SCC of tongue
Among 100 patients, cervical lymph node metastases were found in 22 patients (group pN+) during the periods of follow-up. Therefore, the rate of OCLNM in patients with SCC of the tongue was 22% (22/100).
According to the Memorial Sloan-Kettering classification of node levels,10 OCLNM in one level was found in 14 patients. Among them, there was 1 patient in level I, 9 patients in level II, 1 patient in level III and 3 patients in level IV. OCLNM in two levels were found in 7 patients, there was 1 patient in levels I and II, 5 patients in levels II and III, 1 patient in levels III and IV. And OCLNM in levels I—III was found in 1 patient. In summary, a total of 31 levels in ipsilateral necks were found OCLNM in 22 patients (group pN+). The most common region with OCLNM was the level II and the percentage was 51.61% (16/31). The second most common was level III and the percentage was 25.81% (8/31). The third most common was levels I and IV, and the percentage was 9.68% (3/31). The percentage of OCLNM in levels I—III was 87.10% (27/31). OCLNM in level V was found only in 1 patient (3.23%). No OCLNM in the contralateral neck was found in this study (Table 1).
Twenty-eight patients underwent “wait and see” policy. During the periods of follow-up, cervical lymph node metastases were found in 10 patients (35.71%). Among 72 patients who underwent neck dissection, cervical lymph node metastases were found in 9 patients by postoperative pathological examinations and in 3 patients during the periods of follow-up (Table 2). OCLNM were found within 6 months postoperatively in a majority of patients, the longest time was 20 months and the shortest time was 21 days.
The relations between OCLNM in patients with cN0 SCC of the tongue and clinical and pathological factors
There were 60 patients with grade I, 35 patients with grade II and 5 patients with grade III according to the pathological grading. The rates of occult metastases were 16.67% in grade I, 25.71% in grade II and 60.00% in grade III. The rates of occult metastases were 17.11% in G1, 31.58% in G2 and 60% in G3 according to degrees of differentiation. The rates of occult metastases were 15.71% in 70 patients with tumors in the mucosal layer, 25.00% in 24 patients with tumors in the submucosal layer, and 83.33% in 6 patients with tumors in the muscular layer. The rates of occult metastases were 22.22% in tumors with diameters of ≤3 cm and 21.62% in tumors with diameters of ≥3 cm. For the forms of tumor growth, the rates of occult metastases were the highest in the infiltrative form (44.44%), the lowest in the exophytic form (10.21%) and medial in the ulcerative form (27.27%) (Table 3). By Cochran-Armitage trend test and Exact Propability test, there was a significant difference in occult metastases among groups according to pathological grades, degree of differentiation, depth of invasion, forms of growth and T classifications (P <0.05). And there was no significant difference between the T1 and T2 groups (16% vs 16.67%). There was also no significant difference among groups in diameter of the tumor (P >0.05). Furthermore, the rate of occult metastases was increased as the depth of invasion increased, the pathological grade advanced, and the degree of differentiation declined.
At present, there are three options in neck treatment for patients with cN0 SCC of the tongue.11 The first one is FND or elective radiotherapy.12 The second one is SOND, the lymph nodes with doubtful metastases are examined by frozen sections to decide whether RND should be performed or not. The third one is “wait and see”,13 salvage surgery is not performed until the metastatic lymph nodes are observed so that overtreatment for cN0 patients can be avoided. However, this retrospective study indicates that 16% and 16.67% of OCLNM can be found in patients with T1 and T2 classifications, respectively. In the present condition, no clinical examinations or biochemical indicators can be used to assess the metastatic condition of the cervical lymph node accurately. Therefore, the hotspots are to provide evidence for neck dissection in management of cN0 patients with SCC of the tongue by analyzing the distribution characteristics of OCLNM and to add theory for postoperative follow-up by exploring the emergence time of metastases. 14 The aim of these studies was to avoid overtreatment or undertreatment which can influence the prognosis of the patients. The present study indicates that there is a law for the OCLNM in SCC of the tongue. The most common region with OCLNM is level II in the ipsilateral neck, the second most one is level III, and the third most common one is levels I and IV. The percentage of OCLNM in levels I—III is 87.10% (27/31). Therefore, the levels I—III in the ipsilateral neck are the important regions to be dissected in SND. As shown by a similar study,15 the incidence of occult metastases only in the levels IV-V (skip metastases) in ipsilateral neck was 0.6%-3.0%. That is to say, the most common lymph nodes with occult metastases can be removed by SOND (levels I—III) in the ipsilateral neck. The present study also indicates the incidence of occult metastases in levels IV-V are low, which is similar to the outcomes of Hamakawa et al15 and Barrera et al.16 Because the injuries by SOND to the patient’s function and contour are milder than those of RND and FND,17–19 we propose SOND should be the first elective treatment to the neck in patients with cN0 SCC of the tongue and the lymph nodes in level IIb should be included. By this approach, it not only avoids overtreatment20 for the neck in cN0 SCC of the tongue but is also a remedy for undertreatment in “wait and see”. The limitation of present study is the small number of patients so that the conclusion can be influenced by some factors, such as the different groups and the periods of the follow-up. As to the time of emergence of OCLNM, Yang et al21 proposed that the most common occult metastases in cN0 SCC of the tongue were found within 2 years after the first treatment. This study shows OCLNM are found within 6 months postoperatively in a majority of patients; the longest time was 20 months and the shortest time was 21 days after the first treatment. Therefore, the periods of follow-up are at least more than 2 years. Among the relations between OCLNM in patients with cN0 SCC of the tongue and clinical and pathological factors, we find occult metastases are not correlated with the diameter of the tumor (P >0.05), but statistically correlated with the depth of invasion (P <0.05). Therefore, there are limitations to assess the cervical metastases by the diameter of tumor while the depth of invasion is a better index than the former. The present study also shows that occult metastases are correlated with higher pathological grades and a poorer degree of differentiation according to histological grades based upon the classification of the World Health Organization in 1997. Furthermore, the rate of occult metastases in the infiltrative form (44.44%) is remarkably higher than that of the ulcerative form (27.27%) and the exophytic form (10.21%). There is a significant difference among these three groups.
In conclusion, the most common region with OCLNM is levels I—III in the ipsilateral neck. In OCLNM patients with cN0 SCC of the tongue there are statistically significant correlations with the forms of tumor growth, depth of invasion, the degree of differentiation and pathological grade. The rate of occult metastases increases as the pathological grade increases, with the degree of differentiation declining and with the depth of invasion increasing. We advocate that the treatment for patients with cN0 SCC of the tongue should include careful consideration of the pathological grade, the form of tumor growth, the depth of invasion and the degree of differentiation. SND can be performed in patients with high incidence of cervical lymph node metastases and the period of follow-up should be more than 2 years. The treatment of “ wait and see” without consideration of the above-mentioned factors is not acceptable.
1. Schmalbach CE, Miller FR. Occult primary head and neck carcinoma. Curr Oncol Rep 2007; 9: 139-146.
2. Sano D, Myers JN. Metastasis of squamous cell carcinoma of the oral tongue. Cancer Metastasis Rev 2007; 26: 645-662.
3. Montes DM, Schmidt BL. Oral maxillary squamous cell carcinoma: management of the clinically negative neck. J Oral Maxillofac Surg 2008; 66: 762-766.
4. Huang SF, Kang CJ, Lin CY, Fan KH, Yen TC, Wang HM, et al. Neck treatment of patients with early stage oral tongue cancer: comparison between observation, supraomohyoid dissection, and extended dissection. Cancer 2008; 112: 1066-1075.
5. Guo ZM, Zeng ZY, Chen FJ, Peng HW, Wei MW, Zhang Q, et al. Management option for cervical metastases in tongue squamous cell carcinoma with clinically N0 neck. Chin J Otorhinolaryngol Head Neck Surg (Chin) 2005; 40: 91-94.
6. Han QB, Zhang WF. The analysis of 203 tongue cancer patients on recurrence factors. J Oral Sci Res (Chin) 2005; 21: 321-323.
7. Greene FL, Page DL, Fleming ID, Fritz A, Balch CM, Haller DG, et al. American Joint Committee on cancer. AJCC cancer staging manual. 6th ed. New York: Spring; 2002: 17-77.
8. Yuen AP, Lam KY, Wei WI, Lam KY, Ho CM. A comparison of prognostic significance of tumor diameter, length, width, thickness, area, volume and clinicopathological features of oral tongue carcinoma. Am J Surg 2000; 180: 139-143.
9. Longjiang L, Yuming W, Changmei W, Lijuan W. Rational radical neck dissection for oral cancer. Chin Med J 2003; 116: 1123-1126.
10. Leedy DA, Trune DR, Kronz JD, Weidner N, Cohen JI. Tumor angiogenesis the p53 antigen and cervical metastasis in squamous cell carcinoma of the tongue. Otolaryngol Head Neck Surg 1994; 111: 417-422.
11. KhafifA, Lopez-Garza JR, Medina JE. Is dissection of level IV necessary in patients with T1-T3N0 tongue cancer? Laryngoscope 2001; 111: 1088-1090.
12. Terada A, Hasegawa Y, Goto M, Sato E, Hyodo I, Ogawa T, et al. Sentinel lymph node radiolocalization in clinically negative neck oral cancer. Head Neck 2006; 28: 114-120.
13. Kowalski LP, Bagietto R, Lara JR, Santos RL. Prognostic significance of the distribution of neck node metastasis from oral carcinoma. Head Neck 2000; 22: 207-214.
14. Kovács AF, Döbert N, Walendzik H, Zaplatnikov K, Landes CA. The diagnostic role of radioactivity in sentinel nodes in oral and oropharyngeal cancer. Cancer Biother Radiopharm 2006; 21: 535-543.
15. Hamakawa H, Takemura K, Sumida T, Kayahara H, Tanioka H, Sogawa K. Histological study on pN upgrading of oral cancer. Virchows Arch 2000; 437: 116-121.
16. Barrera JE, Miller ME, Said S, Jafek BW, Campana JP, Shroyer KR. Detection of occult cervical micrometastases in patients with head and neck squamous cell cancer. Laryngoscope 2003; 113: 892-896.
17. Taylor RJ, Chepeha JC, Teknos TN, Bradford CR, Sharma PK, Terrell JE, et al. Development and validation of the neck dissection impairment index: a quality of life measure. Arch Otolaryngol Head Neck Surg 2002; 128: 44-49.
18. Saffold SH, Wax MK, Nguyen A, Caro JE, Andersen PE, Everts EC, et al. Sensory changes associated with selective neck dissection. Arch Otolaryngol Head Neck Surg 2000; 126: 425-428.
19. Keski-Säntti H, Kontio R, Leivo I, Törnwall J, Mätzke S, Mäkitie AA, et al. Sentinel lymph node biopsy as an alternative to wait and see policy in patients with small T1 oral cavity squamous cell carcinoma. Acta Otolaryngol 2008; 128: 98-102.
20. Aarts MC, Hogen Esch TT, Terhaard CH, Koole R, Hordijk GJ. Guidelines in head and neck oncology compliance and consequences of deviations from the standard protocol for tongue and floor of mouth squamous carcinoma. Clin Otolaryngol 2005; 30: 444-450.
21. Yang AK, Chen FJ, Li QL, Wei MW, Song M. Characteristics of occult cervical lymph node metastasis in squamous cell carcinoma of tongue and their influence on prognosis. Cancer (Chin) 2003; 22: 541-544.